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Electronic Cigarettes and Vaping: A New Challenge in Clinical Medicine and
Public Health. A Literature Review
Article in Frontiers in Public Health · November 2013
DOI: 10.3389/fpubh.2013.00056 · Source: PubMed
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PUBLIC HEALTH
REVIEW ARTICLE
published: 18 November 2013
doi: 10.3389/fpubh.2013.00056
Electronic cigarettes and vaping: a new challenge in
clinical medicine and public health. A literature review
Dominic L. Palazzolo*
Department of Physiology and Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN, USA
Edited by:
SangNam Ahn, The University of
Memphis School of Public Health,
USA
Reviewed by:
Laura Rudkin, University of Texas
Medical Branch, USA
Sandie Uyen Ha, University of Florida,
USA
*Correspondence:
Dominic L. Palazzolo, Department of
Physiology and Pharmacology,
DeBusk College of Osteopathic
Medicine, Lincoln Memorial
University, 6965 Cumberland Gap
Parkway, Harrogate, TN 37752, USA
e-mail: dominic.palazzolo@
lmunet.edu
Electronic cigarette (e-cigarette) use, or vaping, in the United States and worldwide is
increasing. Their use is highly controversial from scientific, political, financial, psychologi-
cal, and sociological ideologies. Given the controversial nature of e-cigarettes and vaping,
how should medical care providers advise their patients?To effectively face this new chal-
lenge, health care professionals need to become more familiar with the existing literature
concerning e-cigarettes and vaping, especially the scientific literature. Thus, the aim of
this article is to present a review of the scientific evidence-based primary literature con-
cerning electronic cigarettes and vaping. A search of the most current literature using the
pubmed database dating back to 2008, and using electronic cigarette(s) or e-cigarette(s) as
key words, yielded a total of 66 highly relevant articles. These articles primarily deal with
(1) consumer-based surveys regarding personal views on vaping, (2) chemical analysis of
e-cigarette cartridges, solutions, and mist, (3) nicotine content, delivery, and pharmacoki-
netics, and (4) clinical and physiological studies investigating the effects of acute vaping.
When compared to the effects of smoking, the scant available literature suggests that vap-
ing could be a “harm reduction” alternative to smoking and a possible means for smoking
cessation, at least to the same degree as other Food and Drug Administration-approved
nicotine replacement therapies. However, it is unclear if vaping e-cigarettes will reduce or
increase nicotine addiction. It is obvious that more rigorous investigations of the acute and
long-term health effects of vaping are required to establish the safety and efficacy of these
devices; especially parallel experiments comparing the cardiopulmonary effects of vaping
to smoking. Only then will the medical community be able to adequately meet the new
challenge e-cigarettes and vaping present to clinical medicine and public health.
Keywords: electronic cigarettes, nicotine addiction, nicotine replacement, smoking cessation, vaping, harm
reduction
INTRODUCTION
Use of electronic cigarettes (e-cigarettes), referred to as vaping,
is a relatively new phenomenon that is quickly gaining the inter-
est of many long-time tobacco smokers. According to a report by
UBS Securities LLC (1), sales from the e-cigarette market dou-
bled from $250 to $500 million between 2011 and 2012, and
are expected to quadruple by 2014. E-cigarettes are becoming a
preferred alternative for nicotine delivery among many smok-
ers because of their realistic look, feel, and taste compared to
traditional cigarettes. Furthermore, many cigarette smokers have
turned to vaping because e-cigarette vendors have previously mar-
keted their product as a cheaper and safer smokeless alternative to
traditional cigarettes, and a possible smoking cessation tool. The
Food and Drug Administration (FDA) rejected these claims, and
in September of 2010 they informed the President of the Electronic
Cigarette Association (2) that warning letters had been issued to
fivedistributorsof e-cigarettesfor“violationsof goodmanufactur-
ing practices, making unsubstantiated drug claims, and using the
devices as delivery mechanisms for active pharmaceutical ingre-
dients.” Many web sites still claim that use of e-cigarettes is safe
because tobacco is not burned and hence there is no inhalation of
the many toxins found in cigarette smoke. For example, Electronic
Cigarette Consumer Reviews (3), an e-cigarette website, is filled
with anecdotal consumer claims relating how e-cigarettes helped
them to quit smoking and improved their overall health.
The FDA has reported that e-cigarette cartridges and solutions
contain nitrosamines, diethylene glycol, and other contaminants
potentially harmful to humans (4). From their analysis, the FDA
reasons that the sale of e-cigarettes should be prohibited or reg-
ulated as dangerous nicotine delivery systems that comply with
the safety standards of the Federal Food Drug and Cosmetic Act
(FDCA) (5). This presents an obvious dilemma since traditional
cigarettes, which include nicotine, are proven to be harmful to
human health, but are exempt from the FDCA safety standards.
After Smoking Everywhere, Inc., filed an injunction against the
FDA for restricting the sale of their e-cigarettes in the United
States (6), the US Court of Appeals (7) decided that e-cigarettes
may not be marketed as a safer alternative to cigarettes, or as a
smoking cessation device, but instead must be sold as a smoke-
less tobacco product subject to the same rules and regulations
of other tobacco products. What makes this ruling so controver-
sial is that e-cigarettes contain no tobacco other than a miniscule
www.frontiersin.org November 2013 | Volume 1 | Article 56 | 1

Palazzolo Electronic cigarettes: a new challenge
quantity found in the tobacco flavoring. Despite the court’s deci-
sion, e-cigarette vendors have embraced this ruling, and are happy
to sell their devices as alternatives to conventional cigarettes, so
long as the FDA does not interfere with the sale of their prod-
ucts. Nevertheless, the potential harmful effects of vaping have led
the FDA to issue Internet warnings regarding the risks of vap-
ing (8). While the FDA has serious concerns regarding their use,
Health New Zealand Ltd. (HNZ), a private enterprise which ana-
lyzed the safety of the Ruyan® e-cigarette with Ruyan® financial
support, recommends the use of e-cigarettes as an alternative to
traditional smoking (9). HNZ bases its recommendation on the
likelihood that vaping is potentially less dangerous than tradi-
tional smoking; in other words,their message is“harm reduction.”
Cahn and Siegel (10) support HNZ’s recommendation, conclud-
ing that “electronic cigarettes show tremendous promise in the
fight against tobacco-related morbidity and mortality.” In addi-
tion to reducing tobacco-related morbidity and mortality, vaping
may also reduce harm incurred from second hand smoke and
benefit the environment (11).
Foulds et al. (12, 13) believe that more research needs to be
conducted to determine the safety and efficacy of e-cigarettes as a
smoking cessation tool. However, they also state that individuals
who have successfully quit smoking in favor of vaping should con-
tinue to use e-cigarettes as a healthier alternative to conventional
cigarettes. Although there are clear perceptions among e-cigarette
users that e-cigarettes can be used as both a smoking cessation
tool, and a safer alternative to smoking, they can be marketed as
neither. The FDCA (5) precludes their use as a smoking cessation
tool, and the Family Smoking Prevention and Tobacco Control
Act (14) precludes their use as a reduced-risk alternative; there-
fore, e-cigarettes must be sold as a tobacco product. E-cigarettes
could play an important role in the future of smoking cessation,
but their use is currently clouded by a tangle of legal and political
issues. It is evident that more research on the safety and efficacy
of e-cigarettes needs to be conducted, and that more stringent
quality control measures should be implemented in order for the
legal and political ramifications surrounding these products can
be untangled.
The medical community must prepare itself to face the new
challenge concerning e-cigarettes and vaping as a “harm reduc-
tion” tool. As a consequence of past lessons learned from “Big
Tobacco” companies, the medical community is suspicious of e-
cigarettes and has routinely advised against their use (15). The
medical community advises on the side of caution, indicating that
very little scientific evidence is available to show, one way or the
other, that e-cigarettes are safe to use, or that they help in the
smoking cessation process. In addition, many physicians fear that
patients who vape are merely substituting one form of nicotine
addiction for another. While there are certainly potential perils
associated with vaping, smoking, the leading cause of preventable
disease in the United States, is likely to be more dangerous than
vaping, especially when considering the myriad of known toxins
found in cigarette smoke and the diseases which they promote.
Assuming this premise is true, what should the primary med-
ical focus be for a patient who has successfully transitioned from
conventional cigarettes to e-cigarettes? Should it be to maintain
smoking abstinence, or should it be to quit vaping? Would it not
be prudent for a patient who is unwilling to quit smoking or give
up nicotine to vape instead of smoke? Given these circumstances,
how should patients be advised? The potential health hazards of
nicotine addiction from smokeless tobacco products have pre-
viously been reviewed in a policy statement by the American
Heart Association and include hemodynamic effects, endothelial
dysfunction, thrombogenesis, systemic inflammation, and other
metabolic effects (16). Understandably, the medical community
(15) is concerned that increased availability of e-cigarettes could
increase worldwide nicotine dependence, especially among the
young as they are enticed by the various flavor options e-cigarettes
have to offer. Since vaping does not produce smoke from burning
tobacco, the opponents of e-cigarettes fear that traditional smok-
ers will substitute vaping for smoking in settings where smoking
is not permitted without any real intention of quitting conven-
tional cigarettes. Furthermore, vaping in public places, coupled
with recent e-cigarette commercials on national television, could
possibly undermine or weaken current antismoking regulations.
Health care professionals will need to consider and weigh what
is more harmful to the public, continued smoking or increased
nicotine addiction. As e-cigarettes gain greater popularity among
smokers, these challenges will undoubtedly occur with increasing
frequency.
In order to face this new challenge, health care professionals
will need to become familiar with the available scientific evidence-
based literature concerning e-cigarettes and vaping. Currently,this
literature is sparse, but growing fast, and primarily deals with (1)
consumer-based surveys regarding personal views on vaping, (2)
chemical analysis of e-cigarette cartridges, solutions, and mist, (3)
nicotine content, delivery, and pharmacokinetics, and (4) clinical
and physiological studies investigating the acute effects of vap-
ing. Only after reviewing the current literature can physicians and
other health care providers give appropriate counsel regarding the
role of e-cigarettes and vaping as a safer alternative to smoking,
and as a smoking cessation tool (17). Consequently, the aim of
this article is to provide a review of the current literature concern-
ing e-cigarettes and vaping so that the medical community can
better prepare for the new challenge these devices bring to clini-
cal medicine and public health. The search for relevant scientific
literature was accomplished using the pubmed database in which
the key words electronic cigarette(s) or e-cigarette(s) were used.
The search for articles extended back to 2008 and only highly rel-
evant evidence-based primary literature was retrieved for review.
Sixty-six articles dealing with surveys soliciting personal views on
vaping; studies analyzing potential toxins and contaminants in e-
cigarette cartridges, solutions, and mist; reports profiling nicotine
content, delivery, and pharmacokinetics; and clinical and phys-
iological studies investigating the effects of acute vaping were
ultimately used. Of these articles, two were published between
2008 and 2009. Six,ten,and fifteen articles were published in 2010,
2011, and 2012, respectively. Thus far, 33 highly relevant articles
have been published in 2013, indicating a progressive increase in
e-cigarette related research.
CONSUMER-BASED SURVEYS
Surveys have shown that awareness of e-cigarettes has quadrupled
between 2009 and 2011 (18) and that they have a high adoption
Frontiers in Public Health | Public Health Education and Promotion November 2013 | Volume 1 | Article 56 | 2

rate among traditional smokers (19, 20). Many current and ex-
smokers use e-cigarettes as a nicotine replacement therapy (NRT)
to help them reduce or quit smoking (13, 21–25) while others use
e-cigarettes as a less harmful alternative to smoking (21,23,26,27).
At the end of 6 months, Polosa et al. found that vaping e-cigarettes
decreased consumption of conventional cigarettes by 80% after
6 months (28) and 50% after 24 months (29). Caponnetto et al.
reported similar reductions in cigarette consumption and ciga-
rette abstinence after a year-long trial of using e-cigarettes in both
normal smokers (30) and in chronic schizophrenic smokers (31).
The authors claim that withdrawal symptoms were minimal and
that the perception and acceptance of e-cigarettes was satisfactory,
even in the schizophrenic patients. The results of Vickerman et al.
(32) are less optimistic. They reported that nearly a third of 2758
callers to six state tobacco quit lines had ever used e-cigarettes of
which 61.7% used the e-cigarettes for <1 month. Barbeau et al.
(26) reported that using e-cigarettes, in comparison to other FDA-
approved NRTs, such as nicotine gum, patches, and inhalers, had
less annoying side effects and were more effective in prevent-
ing relapse, primarily because vaping retained the psychosocial
aspects of real smoking better than the FDA-approved NRTs. Hua
et al. (33) found a total of 405 different health-related effects
(78 positive, 326 negative, and 1 neutral) reported by e-cigarette
users in three different online forums. Users reporting negative
health-related effects often reported multiple symptoms, while
users reporting positive health-related effects usually reported
a single symptom. Additionally, negative health-related effects
occurred most frequently in the respiratory, neurological, sen-
sory, and digestive systems while the positive health-related effects
occurred solely in the respiratory system.
It is possible that the decreased daily consumption of conven-
tional cigarettes among e-cigarette users, as seen in some studies
(28–31), is at least partially due to a psychological element involv-
ing smokers’ motivation to quit. Support for this idea is seen in a
recent Hawaiian multiethnic study (34) involving 1567 traditional
smokers of which 13% were also e-cigarette users attempting to
quit smoking. This survey reported that smokers who used e-
cigarettes as a smoking cessation tool were more serious about
wanting to quit smoking as compared to smokers who did not use
e-cigarettes. In addition, e-cigarettes were also viewed as a viable
option to other FDA-approved smoking cessation tools. Sutfin
et al. (35) surveyed 4444 students from eight North Carolina col-
leges and found that 216 of these students had experimented with
e-cigarettes (ever e-cigarette users) while 4228 had never used e-
cigarettes (never e-cigarette users). Of the ever e-cigarette users,
12% were never smokers,30% were former or experimental smok-
ers, 33% were current non-daily smokers, and 9% were current
daily smokers compared to 53, 19, 14, and 4%, for the never
e-cigarette users, respectively. When the ever e-cigarette users
were asked about e-cigarette harm perception, 17% indicated e-
cigarettesareasharmfulasconventionalcigarettes,45%responded
with less harmful, 3% thought e-cigarettes to be more harmful,
and 23% were unsure. The never e-cigarette users responded with
16, 22, 2, and 51%, respectively. This data suggest that vaping
is more common, but not exclusive, among traditional smokers.
Another statistic revealed that vaping among young college stu-
dents (mean age 20.7 ± 2.9 years) does not appear to be motivated
by any intention to quit smoking. This is somewhat in contrast to
Pokhrel et al. (34) who indicated more serious intentions toward
smoking cessation among an older population of smokers using
e-cigarettes (mean age 42.3 ± 1.02 years) compared to smokers
not using e-cigarettes (mean age 45.63 ± 0.35 years). They also
reported that individuals who took up vaping as a means to quit
smoking were significantly younger and had smoked for less years
than those who never vaped.
A concern of the FDA (8) and the medical community (15) is
that availability of e-cigarettes will entice teens and young adults
toward vaping, which could ultimately lead to smoking conven-
tional cigarettes. Currently, there is little or no concrete evidence
confirming the validity of this concern. Cho et al. (36) used data
collectedfromaKoreanHealthProjecttodetermineawarenessand
use of e-cigarettes. They found that 10.2% of 4353 students were
aware of e-cigarettes, but only 0.5% of those students had actually
tried e-cigarettes. Pepper et al. (37) conducted a national online
survey of 228 male adolescents (ages 11–19) and determined that
<1% of these individuals actually tried e-cigarettes. On the other
hand, 67% of the respondents were aware of e-cigarettes with
awareness being higher among the older boys. Of those individu-
als who never tried e-cigarettes, 18% were willing to experiment
with no preference toward flavored versus unflavored e-cigarettes.
Additionally, smokers were more amiable to experiment with e-
cigarettes than non-smokers. In contrast,discussions with 11 focus
groups involving 66 young adults (ages 18–26) revealed that young
adults favorably perceive e-cigarettes and other new tobacco prod-
ucts specifically because they come in different flavors and that
eliminating these flavors may reduce intentions to try these prod-
ucts (38). Another study surveyed 2624 US Midwestern young
adults (ages 20–28) and indicated that 69.9% of the respondents
were aware of e-cigarettes, but that only 7% actually tried vap-
ing (39). Goniewicz et al. (40) conducted a survey of students
enrolled at 176 nationally representative Polish high schools (ages
15–19) and universities (ages 20–24) and reported that 23.5% of
high school students and 19% of university students had ever tried
e-cigarettes. Of all the students who tried e-cigarettes, only 3.2%
were non-smokers, which compares closely to the 4.9% reported
by Sutfin et al. (35). Other strong correlates of e-cigarette use
among adolescents include male gender, and having parents who
smoke (36, 40). While a small percentage of young non-smokers
experiment with e-cigarettes, it is more likely that young smok-
ers will experiment with e-cigarettes. One fact emerges from these
studies; as e-cigarette popularity increases, so does awareness of
them among young individuals. How increasing awareness will
ultimately affect e-cigarette usage by adolescent and young adults
remains to be seen.
A number of studies (41–43) indicate that all forms of NRT
are at least initially successful in maintaining cigarette abstinence.
However, the successful long-term smoking cessation rate still
remains relatively low. Employing a meta-analysis study, Hughes
et al. (41) found the 6-month smoking quit rates for NRTs to be
between 1 and 11% in seven studies as compared to between 3
and 5% in smokers who tried to quit on their own (44). Rennard
et al. (42) reported a quit rate of 8% among smokers who used
the nicotine inhaler for 15 months. In contrast, few studies have
tested e-cigarettes as a smoking cessation tool (28, 29, 45). From

an online survey, Siegal et al. (45) reported that 31% (69 of 216) of
the respondents were no longer smoking cigarettes after 6 months
of using e-cigarettes. Of those respondents who quit smoking,
57% were still using e-cigarettes, 9% were using other tobacco free
nicotine products, and 34% were completely nicotine free. Polosa
et al. (28) investigated the effect of e-cigarettes on smoking cessa-
tion and discovered that 22.5% (9 of 40) of the participants had
not had a cigarette in 6 months. Of that cohort, 67% were still
using e-cigarettes while 33% were nicotine free. Similar results
were reported in a 24-month study by Polosa et al. (29). These
studies and others (46, 47) suggest that e-cigarettes could play a
role in smoking reduction and cessation, and as a result could
reduce the harm incurred by smoking as effectively as any FDA-
approved NRT. However, the role of e-cigarettes on total nicotine
abstinence is still highly questionable, and it has been suggested
that one form of nicotine addiction is simply replacing another
(26). A summary of the studies involving consumer-based surveys
regarding personal views of vaping are shown in Table 1.
CHEMICAL ANALYSIS OF E-CIGARETTE CARTRIDGES,
SOLUTIONS, AND MIST
The ingredients found in e-cigarette cartridges and solutions
are relatively few, and for the most part non-toxic and non-
carcinogenic, especially in the low quantities delivered. They
include nicotine, propylene glycol, glycerin, and tobacco flavor-
ing (4, 48). Propylene glycol, an FDA-approved solvent used in
foods, a vehicle for intravenous diazepam, and as the major ingre-
dient found in e-cigarette fluids, makes up about 90% of the
solution (9). Certain contaminates, most of which are derived
from tobacco flavoring, have been detected in e-cigarettes. A small
amount of diethylene glycol (approximately 1%), a known car-
cinogen and an ingredient in anti-freeze, was also detected in one
out of 18 cartridges analyzed by the FDA (4). The source of the
diethylene glycol contamination is not clear but could reflect the
use of non-pharmaceutical grade propylene glycol (10). In com-
parison, cigarette smoke from burned tobacco products contains
thousands of compounds, many of which have been shown to
induceorpromotecarcinogenesis(49);specificallythetracemetals
(i.e., cadmium, arsenic, chromium, nickel, and lead), the tobacco
specific N-nitrosamines (TSNA), the polycyclic aromatic hydro-
carbons (PAHs), and the volatile organic compounds (VOCs).
While investigations have shown some of these hazardous com-
pounds to be present in e-cigarette cartridges, solutions, and mist,
there are only a few reports detecting levels of these contami-
nates high enough to be of significant risk to humans. The HNZ
study (9) found levels of arsenic cadmium, chromium, nickel, and
lead to be undetectable in e-cigarette cartridge liquid. In contrast,
Williams at al. (50) found levels of lead, chromium, and nickel in
e-cigarette aerosol to be equivalent to, and in some cases higher
than, what has been reported for cigarette smoke. They indicate
that the primary source of these trace metals are the filaments
inside the e-cigarette cartomizer (i.e., the aerosolizing component
of the e-cigarette), and conclude that improved quality control
of e-cigarette design and manufacturing would greatly reduce the
presence of these trace metals. The FDA (4) and HNZ (9) both
reported that e-cigarettes contain trace amounts of TSNAs, but
the levels found in the e-cigarettes represent only a very small
fraction (0.008 µg/e-cigarette cartridge containing 16 mg of nico-
tine) of what is typically found in traditional cigarettes (6.3 µg/full
flavor Marlboro cigarette) (51). To put this into perspective, an e-
cigarette cartridge is good for about 150–300 puffs while a single
conventional cigarette is good for about 10–15 puffs (52). The
amount of total TSNAs found in other FDA-approved nicotine
products was roughly equivalent to the total amount of TSNAs
found in e-cigarettes (9, 10). Other studies (11, 53–56) confirm
the low levels of TSNAs present in e-cigarette solutions and vapor,
as well as the low or undetectable levels of particulate matter,
trace metals, VOCs, and PAHs, especially when compared to the
amounts present in cigarette smoke.
As previously mentioned (2), the FDA issued warnings to sev-
eral e-cigarette companies for selling e-cartridges and refill solu-
tions containing active pharmaceutical ingredients such as rimon-
abant (Zimulti®) for the purpose of losing weight and reducing
smoking addiction, and tadalafil (the active ingredient in Cial-
is®) for the purpose of increasing sexual capacity. FDA analyses of
these e-cartridges and solutions revealed the presence of amino-
tadalafil and not tadalafil,and the presence of an oxidative product
of rimonabant, as well as rimonabant (57), although the amount
of either of these substances that is able to transfer from liquid to
vapor phase is low (58). Table 2 summarizes the studies involving
chemical analyses of e-cigarette cartridges, solutions, and mist.
NICOTINE CONTENT, DELIVERY, AND PHARMACOKINETICS
E-cigarettes are designed to deliver nicotine in an aerosolized
manner that simulates an authentic smoking experience with-
out the real smoke. In this respect, e-cigarettes are similar to
the FDA-approved nicotine inhaler. Bullen et al. (59) determined
the Ruyan® e-cigarette had a nicotine pharmacokinetic profile
very similar to the Nicotrol® inhaler, but the study’s participants
thought the e-cigarettes were more pleasant to use and produced
less irritation to the mouth and throat. For e-cigarettes, the nico-
tine is delivered through cartridges prefilled with a nicotine solu-
tion or cartridges that the user fills with a nicotine refill solution.
In either case, the nicotine concentration of the solutions or car-
tridges can be purchased in strengths ranging from 0 to 24 mg or
more, according to user preference. Unfortunately, the amounts of
nicotine specified on the labels of various brands of e-cartridges
and solutions have not always been accurate or consistent (60).
The FDA (4, 57, 58) confirmed the ability of e-cigarettes to deliver
nicotine, but stated there is too much variability in the amount of
nicotine delivered per puff of any e-cigarette cartridge for them to
be considered safe. Repeated analysis of a menthol high strength
Njoy® e-cigarette cartridge (18 mg of nicotine) yielded nicotine
deliveries of 26.8, 34.9, and 43.2 µg/100 ml puff. The medium
strength Smoking Everywhere® e-cigarette cartridge (11 mg of
nicotine) and the medium strength Njoy® e-cigarette cartridge
(12 mg of nicotine) delivered 15.7 and 10.6 µg nicotine/100 ml
puff, respectively, and were found to be similar to the 10-mg
Nicotrol® inhaler shown to deliver 15.2 µg nicotine/100 ml puff.
Of major concern is that some e-cartridges and solutions that
were labeled as containing 0 mg of nicotine did in fact contain
some nicotine (4, 57). The FDA (4, 58) also detected small quan-
tities of cotinine, a metabolite of nicotine, and several nicotine
relatedimpuritiestoinclude,anabasine,anatabine,myosmine,and

Table 1 | Studies involving consumer-based surveys regarding personal views on vaping.
Authors (Reference) Study design Participants Participant’s location Key finding
STUDIES REPORTING POSITIVE OR NEUTRAL IMPACT OF E-CIGARETTES,VAPING, OR HARM REDUCTION
Etter (21) Online French survey
at www.StopTabac.ch
81 Respondents, ages
19–65, 77% male, 63%
former smokers, 23% daily
smokers, 13% occasional
smokers
81% France E-cigarettes were used to quit
smoking8% Belgium
6% Canada
5% Switzerland
Cho et al. (36) Survey of adolescents
from five schools
participating in a 2008
Health Promotion
Fund Project
4353 Adolescent students Korea 444 adolescent students had heard
of e-cigarettes. 22 adolescents had
ever tried e-cigarettes. Significant
predictors of e-cigarette use include
male gender and cigarette smoking
experience
Etter and Bullen
(22)
Survey of visitors to
websites and online
discussion forums
3587 Respondents, ages
31–52, 63% male, 70%
smokers, 11% occasional
smokers
62% United States E-cigarette users believe that
e-cigarettes helped them to quit or
reduce smoking, and that vaping is
less toxic than smoking
14% France
6% United Kingdom
4% Switzerland
3% Canada
Foulds et al. (12) Survey conducted at
e-cigarette
enthusiast’s
convention
104 Respondents, mean
age 34 ± 9, 74% male,
88% Caucasian, 78%
smokers
Philly Vapefest, 2011,
Philadelphia, PA
E-cigarette users believe that
e-cigarettes helped them to quit
smoking, and vaping is less harmful
than smoking
Polosa et al. (28) Tracking daily
consumption of
cigarettes for
6 months
40 Subjects (26 males)
began and 27 subjects (18
males) ended 6 months
later
Recruited from the local
hospital staff in Catania, Italy
Vaping e-cigarettes decreased
consumption of traditional
cigarettes as verified by exhaled
carbon monoxide
Mean age 43 ± 9 years
Years smoked 27 ± 9 years
Siegal et al. (45) Online survey of new
e-cigarette users who
recently purchased
Blue e-cigarettes
216 Respondents (72%
male), ages 18–65+ years,
smokers for 5–30+ years
Worldwide. E-mail addresses
were provided for 5000 first
time online e-cigarette
purchasers from the
Blue-cigarette distributor and
served as the pool of
respondents
After 6 months of vaping, 31% of
respondents were no longer
smoking cigarettes
Goniewicz and
Zielinska-Danch
(40)
Survey of students
enrolled in at 176
nationally
representative high
schools and
universities in Poland
20,240 High school
students (15–19 years) and
university students
(20–24 years) 43% of
students were male
Poland About 20% of polish youth have
tried e-cigarettes, but only 3% of
never smokers tried e-cigarettes.
Not clear if e-cigarettes are a
novelty that young people try once.
Significant predictors of e-cigarette
use include male gender and
cigarette smoking experience
Kralikova et al. (19) Interview of people
buying cigarettes
between 10 and 19
October 2011
973 Respondents, average
age 32 years, and 54%
male
Five locations across Prague,
Czech Republic
86% of respondents have heard of
e-cigarettes
(Continued)

Table 1 | Continued
Barbeau et al. (26) Focus group
discussions posing
open ended questions
Nine Men and two
women, ages 18–64 years
Boston University School of
Public Health, Boston, MA,
USA
Vaping was more effective in
maintaining cigarette abstinence
than the FDA-approved nicotine
replacement therapies due to
retention of behavioral and social
components of smoking addiction
Bullen et al. (46) Survey using a
randomized controlled
trial. Participants
recruited via
community
newspapers
E-cigarette Group
(n = 289), age
44 ± 13 years, 38% male.
Nicotine patch Group
(n = 295), age
40 ± 13 years, 38% male.
E-cigarette placebo group
(n-73), 43 ± 12 years, 38%
male
Aukland, New Zealand E-cigarettes, with or without
nicotine (placebo e-cigarette), were
as effective at helping smokers quit
as nicotine patches
Caponnetto et al.
(30)
Regular smokers
recruited between
June 2010 and
February 2011 were
observed for
12 months
300 Participants, mean age
44 ± 13 years, 63% male
and smoke at least 15–25
cigarettes/day
Catania, Italy The use of e-cigarettes, with or
without nicotine, decreased
cigarette consumption and elicited
tobacco abstinence as verified by
exhaled carbon monoxide
Caponnetto et al.
(31)
Chronic schizophrenic
patients were
observed and
surveyed for
12 months
14 Schizophrenic patients
(6 male), mean age
45 ± 13 years and smoked
at least 20–35
cigarettes/day
CTA, Villa Chiara-Psichiatrica
Riabilitativa e Ricerca,
Catania, Italy
The use of e-cigarettes decreased
e-cigarette consumption without
causing significant side effects in
schizophrenic patients
Choi and Forster
(39)
Survey of U.S.
Midwestern adults
Cohort of 2624 adults aged
20–28 years
Midwestern United States Nearly 70% of the respondents
were aware of e-cigarettes, and 7%
had tried e-cigarettes. Significant
predictors of e-cigarette use include
male gender and cigarette smoking
experience
Dawkins et al. (23) Online survey hosted
by the University of
East London with links
from TECC/TWEL
websites
1347 Respondents, mean
age 43 years, 70% male
and 96% Caucasian
Respondents from 33
countries (72% European)
E-cigarettes are primarily used for
smoking cessation, but for a longer
duration than nicotine replacement
therapies
Dockrell et al. (24) Three online surveys
and one focus group.
Respondents were
recruited from panel
of adults in Britains
February 2010 online
population survey
(n = 12,597 for all
respondents with n = 2297
for smokers). April 2010
online smokers’ survey
(n = 1380). February 2012
online population survey
(n = 12,432 for all
respondents with n = 2093
for smokers). March 2010
focus group consisting of
smokers (n = 37)
Great Britain E-cigarette use may bridge the
smoking cessation process.There is
little evidence to suggest that
e-cigarettes is widely used among
never smokers
(Continued)

Table 1 | Continued
Farsalinos et al.
(25)
Recruitment and
survey of subjects
who had completely
substituted
conventional
cigarettes with
e-cigarettes for at
least 1 month
111 Participants, 84%
male, mean age
37 ± 6 years, that smoked
at least 20–30,
cigarettes/day. Participants
had a mean smoking
duration of 37 ± 6 years
and a smoking cessation
duration of 4–11 months
Visitors to a Hospital in
Kallithea, Greece and to an
electronic cigarette
consumers’ internet forum in
Greece
E-cigarettes with higher nicotine
content were more successful in
the smoking cessation process
Goniewicz et al.
(27)
Web-based survey of
e-cigarette users
179 Respondents Poland Participants primarily used
e-cigarettes to cease smoking and
reduce smoking related harm
Kralikova et al. (20) Interview of people
smoking cigarettes on
the street during May
of 2012
2012 Respondents,
average age 34 years, 51%
male
17 cities across the Czech
Republic
About one fifth of smokers who try
e-cigarettes go on to become
regular e-cigarette users
Li et al. (47) Telephone-based
survey by random
digit dialing of the
New Zealand Smoking
Monitor to recruit
current smokers and
recent quitters
840 Current smokers and
recent quitters
New Zealand Only 7% of respondents ever
purchased e-cigarettes, 33%
perceived e-cigarettes as less
harmful than conventional
cigarettes and 41% believed
e-cigarettes are an acceptable
means to smoking cessation
Pepper et al. (37) Online national survey
of male adolescents in
November 2011.
Participants recruited
through parents who
were members of a
panel of U.S.
households
228 Male adolescents,
ages 11–19 years
United States Only 2 of 228 adolescents had ever
tried e-cigarettes.18% of adolescent
who were aware of e-cigarettes
were also willing to try them with
no preference to plain or flavored
Pokhrel et al. (34) Cross-sectional survey
of Hawaiian Islanders
recruited through
newspaper
advertisement from
2010 to 2012
1567 Participants divided
into two groups. Ever
–e-cigarette users (n = 202
students; mean age
42 ± 1 years, 46% male)
and never e-cigarette users
(n = 1365; mean age
46 ± 0.4 years, 51% male)
Hawaiian Islands Smokers who try e-cigarettes
appear to be more serious about
smoking cessation and treat
e-cigarettes as valid alternatives to
FDA-approved nicotine replacement
therapies
Polosa et al. (29) Tracking daily
consumption of
cigarettes for
24 months
Follow-up observational
study of Polosa et al. (28).
See above
Recruited from the local
hospital staff in Catania, Italy
Long-term e-cigarette use can
substantially decrease conventional
cigarette consumption as verified by
Regan et al. (18) Consumer-based
mail-in survey
10587 Adult (18 years or
older) respondents in 2009
and 10328 adult (18 years
or older) respondents in
2010
United States Awareness of e-cigarettes doubled
from 16% in 2009 to 32% in 2010
(Continued)

Table 1 | Continued
Sutfin et al. (35) Web-based survey in
fall of 2009
4444 Students divided into
two groups. Ever
e-cigarette users (n = 216
students; mean age
21 ± 3 years, 53% male)
and never e-cigarette users
(n = 4228; mean age
21 ± 3 years, 36% male)
Students from eight North
Carolina colleges
E-cigarette use is more common
among smokers but not exclusive to
them. E-cigarette use among
college students does not appear to
be motivated by intentions to quit
Vickerman et al.
(32)
Survey of callers to six
state tobacco quit
lines 7 months after
initially receiving
intervention
2758 callers United States Only about one third of the
respondents had ever tried
e-cigarettes of which 62% used for
<1 monthThe actual states were not
indicated
STUDIES REPORTING NEGATIVE IMPACT OF E-CIGARETTES,VAPING, OR HARM REDUCTION
Choi et al. (38) Eleven focus group
discussions
66 young adults, ages
18–26 years old
University of Minnesota,
Minneapolis, Minnesota
Young adults perceive e-cigarettes
and other new tobacco products
positively, especially when they are
flavored
Hua et al. (33) Data collected from
postings of three high
traffic online forums
Total of 632 posts from
560 different posters
Worldwide but mostly from
the United States and Canada
A total of 405 different, mostly
negative health-related effects,
were reported by e-cigarette users
β-nicotyrine in some, but not all, e-cartridge solutions and mist
samples analyzed. Flouris and Oikonomou (61) question the rigor
by which the FDA conducted these analyses, indicating that these
analyses “cannot be used to draw conclusions or inferences about
potential effects on health” until more rigorous chemical analy-
ses, followed by extensive animal and clinical trials in humans,
are conducted. Two other studies have also found discrepancies in
the labeled nicotine content compared to the actual nicotine con-
tent in a number of e-cigarette brands (52, 62). Goniewicz et al.
(52) reported relative percent differences between the labeled and
actual nicotine concentration per cartridges (or refill fluids) to
range between −89 and 28% in 30 popular brands of e-cigarettes.
Cameron et al. (62) found the actual nicotine concentration in e-
cigarette cartridges and refill fluids to range from 1.8 to 23.7 mg/ml
less than the labeled nicotine concentration. However, a more
recent study analyzing several brands of e-cigarette refill solu-
tions did find nicotine content to be accurate and consistent to
what was printed on the label (63). Inconsistencies reported in
nicotine concentrations, and hence deliveries, could be a reason
why some e-cigarette users and not others report adverse reac-
tions such as mouth and throat irritation, vertigo, headache, and
nausea (21, 26, 33). Incidentally, some of these same adverse reac-
tions have also been reported for various FDA-approved NRTs
(64). In a study evaluating design features, accuracy and clarity of
labeling, and quality of printed materials and instruction manu-
als for e-cigarettes it was concluded that design flaws, inadequate
product labeling, and lack of quality control in the manufacturing
of e-cigarettes are an indication that stricter oversight and reg-
ulation are required for these devices (65). Accurate production,
safe packaging, and proper storage of e-cigarette refill solutions
are critical. Typically, a 5-ml vial of e-cigarette refill solution could
contain a nicotine concentration of 20 mg/ml or 100 mg/vial, and
the known lethal dose of nicotine has been estimated to be about
10 mg in children and between 30 and 60 mg in adults (62). Given
the potential health hazards of nicotine (16),inadvertent skin con-
tact, or consumption of just one of these vials by children or
pets could have tragic consequences. It is important that extreme
caution be used when storing nicotine solutions.
Regardless of the inaccuracies and inconsistencies in the pro-
duction of e-cigarette cartridges and solutions, puff-for-puff, the
amount of nicotine finding its way into the blood stream from
vaping an e-cigarette has been shown to be less than what you
would expect from smoking a conventional cigarette with com-
parable nicotine content (59, 66, 67). These studies report little
or no increases in blood nicotine levels of naive subjects after
acute predefined use of e-cigarettes compared to conventional
cigarettes. According to Bullen et al. (59), serum levels of nico-
tine were similar after use of either the Nicotrol® inhaler or a
Ruyan® e-cigarette. They found serum nicotine levels to peak at
1.3 ng/ml after 19.6 min of vaping an e-cigarette, and 2.1 ng/ml
after32 minof usingtheNicotrol®inhaler,comparedto13.4 ng/ml
after 14.3 min of smoking a cigarette. The Nicotrol® inhaler is said
to be inappropriately named since it does not deliver significant
quantities of nicotine directly to the lungs (68, 69). This is because
the particle size of the delivered nicotine is too large to effectively
reach pulmonary alveoli (70,71).With each puff,the inhaler deliv-
ers nicotine to the oral cavity which is subsequently absorbed by
the buccal mucosa and pharyngeal mucosa. It is not clear where

Table 2 | Studies involving chemical analysis of e-cigarette cartridges, solutions, and mist.
Authors (Reference) E-cigarette brand Substances tested Analysis Key finding
STUDIES REPORTING POSITIVE OR NEUTRAL IMPACT OF E-CIGARETTES,VAPING, OR HARM REDUCTION BASED ONTHE
ABSENCE OR PRESENCE OF SPECIFICTOXINS
Laugesen (9) Runyon TSNA LC-MS TSNAs are present but at levels much lower than
in conventional cigarettes and too small to be
carcinogenic
Research funded by
Runyan
MAO-A and B
inhibitors
Flourometric assay MAO-A and B are inhibited by tobacco smoke but
unaffected by e-cigarette fluid
PAH GS-MS Polycyclic aromatic hydrocarbons undetectable
Heavy metals ICP-MS Heavy metals were undetectable
CO CO analyzer Exhaled carbon monoxide does not increase after
e-cigarette use
McAuley et al. (11) Brand not indicated. TSNA GC/MS TSNA, PAH, diethylene glycol, VOC, and carbonyls
in e-cigarette mist were all negligible compared to
cigarette smoke.
PAH GC/MS
Diethylene Glycol GC/MS
VOC HS-GC/MS
Carbonyls HPLC-UV
Pellegrino et. al. (56) Italian brand of
e-cigarettes
Particulate matter Particle counter and smoking
machine
Particulate matter is lower in e-cigarette mist
compared to cigarette smoke
Abstract in English
Full article in Italian
Goniewicz et al. (53) Eleven brands of Polish
and one brand of English
e-cigarettes
Carbonyls
VOC
TSNA
Heavy metals
HPLC-DAD
GC-MS
UPLC-MS
ICP-MS
TSNA, VOC, and carbonyl compounds were
determined to be between 9 and 450 times lower
in e-cigarettes mist compared to conventional
cigarette smoke
Heavy metals present in e-cigarette mist
Kim and Shin (55) 105 Replacement liquid
brands from 11 Korean
e-cigarette companies
TSNA LC-MS TSNAs are present at low levels in e-cigarette
replacement liquids
Schripp et al. (54) Three unidentified brands VOC GC-MS VOC in e-cigarette cartridges, solutions, and
aerosolized mist were low or undetectable
compared to conventional cigarettes
Particulate matter Particle counter and smoking
machine
Particulate matter is lower in e-cigarette mist
compared to cigarette smoke
STUDIES REPORTING NEGATIVE IMPACT OF E-CIGARETTES,VAPING, OR HARM REDUCTION BASED ONTHE
PRESENCE OF SPECIFICTOXINS
Westenberger (4) Njoy TSNA LC-MS TSNA present
FDA study Smoking everywhere Diethylene glycol GC-MS Diethylene glycol present
Tobacco specific
impurities
GC-MS Tobacco specific impurities present
Trehy et al. (58) FDA
study
Njoy Nicotine related
impurities
HPLC-DAD Nicotine related impurities present
Smoking everywhere
CIXI
Johnson creek
Hadwiger et al. (57)
FDA study
Brand not indicated Amino-tadalafil HPLC-DAD-MMI-MS Amino-tadalafil present
Rimonabant Rimonabant present
Williams et al. (50) Brand not indicated Heavy metals ICP-MS Heavy metal and silicate particles present in
e-cigarette mistSilicate particles Particle counter and smoking
machine, light and electron
microscopy, cytotoxicity testing,
x-ray microanalysis
TSNA, tobacco specific nitrosoamines; LC-MS, liquid chromatography-mass spectrometry; MAO-A and B, monoamineoxidase A and B; PAH, polycyclic aromatic
hydrocarbons; GS-MS, gas chromatography – mass spectrometry; ICP-MS, inductively coupled plasma – mass spectrometry; CO, carbon monoxide, VOC, volatile
organic compounds; UPLC-MS, ultra-performance liquid chromatography-mass spectrometry; HPLC-DAD-MMI-MS, high performance liquid chromatography-diode
array detector-multi-mode ionization-mass spectrometry.

most of the nicotine from e-cigarettes is primarily absorbed; the
alveoli,the airways or the oral cavity. In vitro evidence suggests that
e-cigarette aerosol particle size and distribution in the respiratory
system is similar to conventional cigarette smoke (72–74). Sahu
et al. (72) found the particle size of mainstream cigarette smoke
to range between 186 and 198 nm and deliveries to the pulmonary
alveoli,tracheal,and bronchiolar airways,and oral cavity were pre-
dicted to be 29.8, 15.2, and 16.3%, respectively. Zhang et al. (73)
determined average e-cigarette aerosol particle diameters to be
approximately 400 nm, and alveolar deliveries to be between 7 and
18%. Zhang et al. (73) also indicate that nicotine delivery is highly
dependent on a number of factors, including vaping technique,
particle evolution, and cloud effects. It is very likely that aerosol
particle size and nicotine delivery via e-cigarettes may have similar
distribution profiles that are intermediate between conventional
cigarettes and the Nicotrol® inhaler.
In contrast to the aforementioned investigations (59, 66, 67),
three other study (75–77) found increased blood levels of nicotine
in experienced e-cigarette users within 5 min of the first puff of
an e-cigarette. Dawkins et al. (76) reported blood nicotine levels
to increase from 0.74 ng/ml baseline to 6.77 ng/ml 10 min after 10
puffs of an e-cigarette, achieving a mean 13.91 ng/ml by the end
of a 1-h ad libitum vaping period. It has also been reported that
cotinine in the saliva (78) and serum (79) of e-cigarette users is sig-
nificantly elevated to levels commonly found in cigarette smokers.
Vansickel and Eissenberg (75) also reported an increase in heart
rate, which is not surprising since smoking and nicotine have long
been known to stimulate heart rate and blood pressure (80, 81). It
is interesting to note that the 2010Vansickel et al. (67) study,and in
Czogala et al. (82), heart rate and nicotine levels were significantly
increased in smokers, but not vapers. However, the 2013 Vansickel
and Eissenberg study (75) reported that both smoking and vaping-
induced similar concomitant increases in heart rate and blood
levels of nicotine. As suggested by Farsalinos et al. (83), this dis-
crepancy could be attributed to differences in experimental design,
and puffing topography of the participants in each study (i.e.,
different daily durations of vaping, experience with e-cigarette
devices, personal puffing characteristics to include the amount of
vacuum created on every puff, and the vaping-induced deposi-
tion of nicotine into the oral cavity and/or size of the aerosolized
particles). Trtchounian et al. (84), determined that smoke/aerosol
density remained fairly constant while puffing on a conventional
cigarette from start to finish (approximately 10 puffs), although
variations did exist between brands of conventional cigarettes. The
aerosol density for e-cigarettes, while higher than conventional
cigarettes in three out of the four brands tested, also remained
fairly constant for the first 10 puffs of a new e-cigarette cartridge.
However, a decremental decrease in aerosol density was observed
as each cartridge approached its terminal life. Consequently, this
decrease in aerosol density would require the person vaping to
generate more vacuum to maintain an aerosol density equivalent
to the initial puffs and could be a reason contributing to longer
puff duration for electronic cigarettes than for conventional cig-
arettes (85). Similar variations in the rate of airflow required to
produce aerosol between and within brands of e-cigarettes were
also reported byWilliams and Talbot (86).According to Goniewicz
et al. (52), these studies demonstrate the importance of the initial
nicotine content, the efficiency of the vaporization process that
determines how much of the nicotine gets aerosolized, and the
individual’s puffing topography on the efficacy of nicotine delivery
from e-cigarettes.
Many smokers claim that smoking cigarettes increases cogni-
tive awareness, reduces stress, and induces a pleasurable feeling
of wellbeing. Consequently, this is what makes smoking cigarettes
so enjoyable and addictive. It is suggested that smoking has some
psychological beneficial effects relating to job performance, vigi-
lance, and mnemonic tasks, and that these effects are induced by
nicotine, the addictive ingredient in tobacco (87). Similar effects
have also been noted in non-smokers after a single dose of nicotine
(88), and it is also worth mentioning that nicotine may have an
ameliorating effect on both Parkinson’s and Alzheimer’s patients
(89). Dawkins et al. (90,91) found a decrease in the desire to smoke
and reduced withdrawal symptoms associated with tobacco absti-
nence (1–10 h) among smokers vaping e-cigarettes with nicotine
in comparison to e-cigarettes without nicotine. Furthermore, the
nicotine from the e-cigarette also improved prospective memory
and working memory performance. Nicotine is a central nervous
system (CNS) stimulant,and as such it is possible that a psycholog-
ical need to enhance cognitive functioning reinforces addiction in
smokers (92). Nicotine is also known to stimulate adrenergic and
dopaminergic neurons in mesolimbic areas of the brain involved
with reinforcing pleasurable reward behavior (93). Monoamine
oxidases (MAO) normally reduce nicotine-induced adrenergic
and dopaminergic activities by oxidizing them to inactive metabo-
lites, and thereby limiting reward behavior. For cigarette smokers,
however,nicotine is made even more addictive by synergizing with
MAO inhibitors known to be present in cigarette smoke (94). Sup-
porting evidence has been shown by Fowler et al. (95, 96) in which
the activities of both MAO-A and MAO-B were reduced in vari-
ous brain regions of smokers but not of non-smokers. Lewis et al.
(94) indicate that there are at least six different MAO inhibitors
present in cigarette smoke. In contrast, Laugesen et al. (9) were
unable to detect any MAO inhibitors in e-cigarette cartridges or
the inhaled aerosol mist. These studies suggest that nicotine from
e-cigarettes and other FDA-approved NRTs may be less addictive
than nicotine from burned tobacco products, and may be the rea-
son why e-cigarette users report a suppression of smoking and
nicotine cravings (59, 66, 67, 90, 91). These investigations support
the rationale behind NRT treatment for smoking cessation, which
is that nicotine from NRTs, and possibly e-cigarettes, does not
occupy the nicotinic receptors to the same extent as nicotine from
tobacco smoke (97). The effect is reducing withdrawal symptoms
and cravings for cigarettes (71, 98) while possibly still providing
some enhanced cognitive awareness and pleasurable reward (92,
93). A summary of the studies involving nicotine content,delivery,
and pharmacokinetics are listed in Table 3.
CLINICAL AND PHYSIOLOGICAL EFFECTS OF ACUTE VAPING
The harmful effects of smoking on human health are obvious
and well documented. In contrast, effects of vaping on human
health are inconclusive due to the extreme paucity of empirical
research investigating the presence of vaping-induced health haz-
ardsand/orbenefits.Fewstudieshaveactuallyreporteddeleterious
effects of vaping. In one report, McCauley et al. (99) present a case

Table 3 | Studies involving nicotine content, delivery, and pharmacokinetics.
Authors
(Reference)
E-cigarette
brand
Devices, substances or
parameters tested
Study design and analysis Key finding
STUDIES REPORTING POSITIVE OR NEUTRAL IMPACT OF E-CIGARETTESANDVAPINGAS COMPAREDTO CONVENTIONAL
CIGARETTES AND SMOKING
Bullen et al.
(59)
Ruyan Nicotine pharmacokinetic
profile was determined in . . .
Plasma nicotine (ng/ml) was
determined by HPLC-EC in participants
who smoked at least 10 cigarettes/day
Vaping e-cigarettes produce a
nicotine pharmacokinetic profile
very similar to the Nicotrol inhalers
but considerably lower than
smoking a cigarette
E-cigarette with 16 mg
nicotine (n = 8)
Nicotrol inhaler with 10 mg
nicotine (n = 10)
Participant’s usual cigarette
(n = 9)
Eissenberg
(66)
Njoy
Crown seven
Plasma nicotine and heart
rate measured before and
after 10 puffs of each device
was determined in the
following groups . . .
Sixteen smokers, naïve to e-cigarettes
were cycled through the four device
groups. Participants were required to
have a 12-h period of cigarette
abstinence before the start of each
device test and 48-h between each
device test
Smoking, but not vaping,
significantly increased plasma
nicotine and heart rate
Njoy (16 mg nicotine)
Crown seven (16 mg nicotine)
own brand cigarette
Sham own brand cigarette
Vansickel et al.
(67)
Njoy
Crown seven
Plasma nicotine, expired
carbon monoxide and heart
rate measured before and
after 10 puffs of each device
were determined in the
Sixteen smokers, naïve to e-cigarettes
were cycled through the four device
groups. Participants were required to
have a 12-h period of cigarette
abstinence before the start of each
device test and 48-h between each
device test
Plasma levels of nicotine, expired
carbon monoxide, and heart rate all
increased after smoking, but not
vaping
Njoy (18 mg nicotine)
Crown seven (16 mg nicotine)
Own brand cigarette
Sham own brand cigarette
Etter and
Bullen (78)
Own brand
e-cigarettes
Salivary cotinine and heart
rate
Experienced e-cigarette users vaped
ad libitum but abstained from
cigarettes or NRTs for 48 h upon which
salivary cotinine was collected and
heart rate determined
Vaping and smoking induce similar
increases in salivary cotinine levels
and heart rate
Czogala et al.
(82)
Brand not
indicated
Systolic pressure
Diastolic pressure
Comparison of hemodynamic
parameters in smokers (n = 42; 50%
male) after smoking a cigarette or
vaping an e-cigarette
Vaping e-cigarettes failed to induce
the typical hemodynamic
parameters associated with
traditional smoking
Abstract in
English Full article
In Polish
Pulse
Heart rate
Dawkins et al.
(91)
White Super Desire to smoke Random allocation of 86 smokers into
one of three groups. Desire to smoke
and withdrawal symptoms rated at 0,
5, and 20 min after vaping ad libitum for
5 min. Attention and working memory
was determined using “The Letter
Cancelation” and “Brown–Peterson
Working Memory” tests
E-cigarettes eliminated nicotine
withdrawal symptoms and desire to
smoke and enhanced working
memory performance, suggesting
efficient nicotine delivery
Nicotine withdrawal
symptoms
Attention and working
memory was determined in
the following groups . . .
E-cigarette (18 mg nicotine)
E-cigarette (0 mg nicotine)
Just hold e-cigarette
(Continued)

Table 3 | Continued
Authors
(Reference)
E-cigarette
brand
parameters tested
Ingebrethesen
et al. (74)
Two different
brands not
specified
E-cigarette aerosol particle
size
Smoking machine and spectral
transmission procedure
Particle size in e-cigarette aerosol
and conventional cigarette smoke
for nicotine delivery are similarCigarette smoke particle size
Vansickel et al.
(77)
Vapor king Plasma nicotine
concentration, heart rate,
urge to smoke cigarette, and
nicotine withdrawal
symptoms tested in four
sessions. Session 1: 10 puffs
of e-cigarette; Session 2:
choice of 10 puffs of
e-cigarette or cash; Session 3:
choice of 10 puffs of
e-cigarette or 10 puffs of
conventional cigarette;
Session 4: choice of 10 puffs
of conventional cigarette or
cash. Each session consisted
of 6 bouts of puffing and
bouts were 30 min apart
Twenty smokers, not currently using
e-cigarettes, were cycled through four
experimental sessions. Participants
were required to have a 12-h period of
cigarette abstinence before the start of
each device test and 48-h between
each device test
No mention of how nicotine was
assayed
E-cigarettes deliver significant
amounts of nicotine, increase heart
rate, and reduce nicotine withdrawal
symptoms and the urge to smoke
Zhang et al.
(73)
Bloog MaxX
fusion
E-cigarette aerosol particle
size
Alveolar delivery
Smoking machine and scanning
mobility particle sizer
E-cigarette aerosol particle diameter
was slightly larger and calculated
alveolar delivery is slightly lower
when compared to cigarette smoke.
Nicotine delivery depends on vaping
technique, particle evolution, and
cloud effect
Dawkins and
Corcoran (76)
First-generation
e-cigarette
(18 mg/ml
nicotine)
Plasma nicotine
Tobacco withdrawal
symptoms
Urge to smoke
Fourteen experienced e-cigarette users
abstinent from smoking and vaping for
12 h before test period
Vaping-induced reliable nicotine
delivery after acute use in
experienced e-cigarette users.
Tobacco-related withdrawal
symptoms and urge to smoke were
reduced
Blood samples collected at baseline
(0 min), after 10 puffs, after 1 h
ad libitum, and after a 2-h rest period
Dawkins et al.
(90)
Tornado Desire to smoke and
prospective memory was
determined in two sessions
Twenty smokers, abstinent for 8–10 h,
cycled through two experimental
sessions. Desire to smoke was
determined using “Single-Item Desire
to Smoke Scale” and “Mood and
Physical Symptoms Scale.”
Prospective memory was measured
using “Cambridge Prospective
Memory Test”
Nicotine from e-cigarettes improves
time-based prospective memory,
suggesting efficient nicotine
delivery
Session 1: e-cigarette (18 mg
nicotine)
Session 2: e-cigarette (0 mg
nicotine)
Etter et al. (63) Twenty models of
the 10 most
popular brands of
refill liquids for
e-cigarettes
Contents of nicotine, nicotine
degradation products, and
nicotine impurities
GC and LC The nicotine content in refill bottles
are close to what is indicated on the
label. Impurities in several brands
are detectable but at levels
considered harmless
(Continued)

Table 3 | Continued
Authors
(Reference)
E-cigarette
brand
parameters tested
Farsalinos
et al. (83)
Nobacco Puff number and duration,
inhalation time, exhalation
time, and nicotine consumed
was determined in the
Forty-five e-cigarette users and 35
smokers (smokers were in a
randomized cross-over design) were
observed for puff number and duration,
and inhalation and exhalation times
using video recordings. Nicotine
consumed (e-cigarette group only) was
measured by loss of weight of liquid in
cartridge using a precision balance
E-cigarette use topography and
conventional cigarette use
topography are different. At least
20 mg/ml nicotine in e-cigarette
liquid is required to deliver the same
amount of nicotine as conventional
cigarettesE-cigarette users (vaping)
Smokers (smoking and vaping
subgroups)
Flouris et al.
(79)
Nobacco Serum cotinine was
determined in . . .
Smokers
Never smokers
Smokers (n = 15) went through a
control session, an active smoking
session, and an active vaping session.
Never smokers went through control,
passive smoking and passive vaping
sessions. LC-MC used to measure
serum cotinine
Acute vaping and acute smoking
induce similar increases in serum
cotinine levels
Goniewicz
et al. (52)
Sixteen popular
brands of
e-cigarettes from
Poland, United
Kingdom, and
United States
Nicotine content in e-cigarette
aerosol
E-cigarette aerosol was generated
using smoking machine. Nicotine
content in aerosol was determined
using GS-TSD
Nicotine in e-cigarette aerosol is
lower than in cigarette smoke.
Efficacy and consistency of nicotine
vaporization between brands is
variable
Hua et al. (85) Various brands Puff duration Analysis of Youtube videos of nine
conventional smokers and 64
e-cigarette users
Longer puff durations may help
e-cigarette users to compensate for
poor nicotine delivery
Exhalation duration
Vansickel and
Eissenberg
(75)
Own brand Plasma nicotine Blood samples were collected at
baseline (0 h), after 10 puffs, after 1 h
ad libitum puffing, and after a 2-h rest
period
Vaping and smoking induce similar
increases in plasma nicotine and
heart rate
Heart rate
Experienced e-cigarette users
(n = 8)
STUDIES REPORTING NEGATIVE IMPACT OF E-CIGARETTES AND VAPING AS COMPAREDTO CONVENTIONAL
CIGARETTES AND SMOKING
Westenberger
(4)
Njoy
Smoking
everywhere
Nicotine content in solutions
and mist
HPLC-UV The nicotine in several e-cigarette
solutions is too variable to be
considered safe. The amount of
nicotine delivered per puff is
inconsistent
FDA Study
Hadwiger
et al. (57)
Brand not
indicated
Nicotine content in solutions HPLC-UV Presence of nicotine in products
labeled as containing no nicotine
FDA Study
Trtchounian
et al. (84)
Liberty stix
Smoking
everywhere
Njoy
Crown seven
versus eight
brands of
conventional
cigarettes
Vacuum required for each puff
Aerosol or smoke density
Manometer coupled to smoking
machine
Absorbance measurement using a
spectrophotometer
More vacuum required to vape than
to smoke. Smoke and aerosol
density remained stable for
conventional and e-cigarettes over
the first 10 puffs. Aerosol density
for e-cigarettes gradually decreased
as e-cigarette life extended to 300
puffs. This is reflected by a gradual
increase in vacuum required for
each puff on the e-cigarette.
(Continued)

Table 3 | Continued
Authors
(Reference)
E-cigarette
brand
parameters tested
Trehy et al. (58)
FDA Study
Njoy Nicotine content in solutions
and nicotine delivery/puff
HPLC-UV
Smoking machine
Nicotine in e-cigarette cartridges
and refill solutions is inaccurately
labeled and nicotine content varies
by manufacturer. The amount of
nicotine delivered per puff is
consistent.
Smoking
everywhere
CIXI
Johnson Creek
Trtchounian
and Talbot (65)
Njoy
Ncig
Liberty stix
Crown seven
Smoking
everywhere
VapCigs
Design flaws and defective
parts
E-cigarettes were purchased online.
Information about the parameters
inspected was obtained via e-mail to
vendors or by visual inspection of the
product and product literature
Design flaws, lack of adequate
labeling, concerns about control and
health issues argue for removal of
e-cigarettes from the market
Labels on cartridges, and
wrappers
Leakiness of cartridges
Disposal documentation
Errors in filling of mail orders
Instruction manual
Truth in advertisement
Williams and
Talbot (86)
Various brands Airflow rate required to
produce aerosol
Pressure drop
Aerosol density
Airflow meter
Manometer
Absorbance measurement using a
spectrophotometer
Significant variability exists between
and within brands of e-cigarettes in
the airflow rate required to produce
aerosol, the pressure drop, the
length of time cartridges last, and
production of aerosol
Cheah et al.
(60)
Twenty different
brands of
e-cigarettes
Nicotine content in cartridges
E-cigarettes quality and
documentation
GC-MS
Visual inspection of the product and
product literature
Variable nicotine content in
cartridges of the same brand, and
inconsistency with product labeling,
along with misleading information
on labels raises concern about
e-cigarette safety
Cameron et al.
(62)
Brands of
e-cigarette
nicotine solutions
and cartridges
tested include . . .
Nicotine content in solutions
and cartridges
LC-MS Nicotine levels in e-cigarette
solutions were too variable to be
considered safe
Vapor liquid
No Brand liquid
Smart Smoke
liquid
BE112 cartridge
Vapor cartridge
HPLC-EC, high performance liquid chromatography – electrochemical detection; GS, gas chromatography; LC, liquid chromatography; GC-TSD, gas chromatography –
thermionic specific detection; HPLC-UV, high performance liquid chromatography – ultraviolet detection; GS-MS, gas chromatography – mass spectrometry; LC-MS,
liquid chromatography-mass spectrometry; NRT, nicotine replacement therapy.
study concerning a 42-year-old woman diagnosed with exogenous
lipoid pneumonia due to e-cigarette use. She presented with a 7-
month history of dyspnea, productive cough, and fevers which
coincided with her use of e-cigarettes. Samples of her sputum, and
bronchoalveolar lavage revealed lipid-laden macrophages. Glyc-
erin, an ingredient added to e-cigarette solutions for the purpose
of producing visual smoke when vaping, was thought to be the
causative agent. Computed axial tomography (CAT) images of
her lungs revealed areas of patchy ground glass superimposed
on interlobular septal thickening, a pattern typical of a restric-
tive ventilatory defect with diffusion impairment, and consistent
with the patient’s diagnosis. Cessation of e-cigarette use resulted in
improvement of her symptoms that was verified by follow-up lung
radiography, however, pulmonary function testing still indicated

mild diffusion impairment. Since the case study does not reveal
if the patient is a current or ex-smoker and for how long, it is
unclear whether the persistent diffusion impairment is a result of
a concurrent or previous smoking habit, the use of e-cigarettes,
or the after effects of lipoid pneumonia per se. In another report,
Vardavas et al. (100) found that 5 min of acute vaping among
healthy smokers had no effect on basic pulmonary parameters
[i.e., forced expiratory volume in 1 s (FEV1), forced vital capacity
(FVC), peak expiratory flow (PEF), or midexpiratory flows at 50
(MEF50) and 75 (MEF75) percent]. This is in agreement Flouris
etal.(79)whoreportedtheFEV1/FVCratioafteracutevapingtobe
non-significantly reduced by 3.0% (79). This study, also reported
the FEV1/FVC ratio after acute tobacco smoking to be signifi-
cantly reduced by 7.2%. Vardavas et al. (100) did find decreased
amounts of exhaled nitric oxide and increased peripheral air-
way resistance and impedance in smokers who vaped for 5 min.
From these results they concluded that acute vaping has “imme-
diate adverse physiological effects similar to some of the effects
observed with smoking” but that the long-term health effects of
vaping are not known and potentially harmful. The authors went
on to qualify their conclusion by stating that although the differ-
ences in exhaled nitric oxide, airway resistance, and impedance
were statistically significant, the differences are probably not clin-
ically important. It is possible that the increased airway resistance
and impedance demonstrated by Vardavas et al. (100) is partially
due to the nicotine inhaled from the e-cigarettes. Evidence for
this is seen in a study reporting that non-smokers who inhaled
nicotine (0–64 mg/ml) showed a dose-dependent increase in both
the amount of coughing and airway obstruction, suggesting that
nicotine stimulates afferent nerve endings in the bronchial mucosa
which then triggers parasympathetic cholinergic pathways leading
to bronchoconstriction (101).
In recent years there has been an effort to clinically use exhaled
nitric oxide as an important non-invasive adjunct to pulmonary
function testing (102) in order to monitor the degree of airway
inflammation and eosinophilia (103, 104) commonly observed
in conditions such as asthma. Unfortunately, interpretation of
exhaled nitric oxide levels in the clinical setting is complex and
confusing requiring adjustments for gender, age, height, respi-
ratory infection, allergies, and smoking (105, 106). Given these
difficulties, its validity is controversial. The major consensus in
the literature is that the amount of exhaled nitric oxide is reduced
in long-time smokers, as compared to non-smokers (105–109). In
addition, it has been shown that smoking cessation is associated
with an increase in exhaled nitric oxide back toward non-smoker
levels (110). A possible mechanism of action for the opposing rela-
tionship of exhaled nitric oxide in smokers versus non-smokers
could be the high levels of carbon monoxide present in ciga-
rette smoke since there is strong evidence suggesting that carbon
monoxide inhibits nitric oxide production by blocking nitric oxide
synthase activity (111, 112). This mechanism is unlikely to occur
with long-term vaping since carbon monoxide levels in e-cigarette
mist are negligible (9). In any case, there is no available literature
showing the long-term effects of vaping on exhaled nitric oxide
or carbon monoxide, although Caponnetto et al. (113) did show
exhaled carbon monoxide levels to decrease from 31 to 4 ppm, 29
to 2 ppm, and 35 to 5 ppm in three individuals who first success-
fully transitioned from conventional cigarettes to e-cigarettes and
then quit e-cigarettes altogether. The first time carbon monoxide
was measured, all individuals were heavy smokers (45 pack/year,
28 pack/year, and 89 pack/year histories). The final time that
exhaled carbon monoxide was measured all individuals had been
smoke- and vape-free for nearly 2 years. Using an experimen-
tal group of “healthy” smokers, Vardavas et al. (100) reported a
decreased fraction of exhaled nitric oxide (FENO) after just 5 min
of vaping (from 13.02 to 10.89 ppb) which they correlated with
airway inflammation and oxidative stress. In their introduction
they state that“smokers have significantly lower concentrations of
FENO – a non-invasive marker of bronchial inflammation – com-
pared with non-smokers.” On the other hand, in their discussion
they state that “nitric oxide is an additional marker that has been
implicated in the pathophysiology of airway diseases associated
with smoking, is strongly correlated with eosinophilic inflamma-
tion and bronchial hyperactivity, and has become an established
marker for assessing oxidative stress, indicating the immediate
effect e-cigarette usage might have on pulmonary homeostasis.”
From these two statements and from their FENO results, it is
unclear whether they mean that smoking and vaping produce less
bronchial inflammation and oxidative stress or more bronchial
inflammation and oxidative stress when compared to not smoking
or not vaping.
Although base levels of nitric oxide tend to be lower in smokers
compared to non-smokers,Chambers et al. (114) observed signifi-
cant increases in exhaled nitric oxide from 2.6 ppb before smoking
to 4.8 ppb 1 min and 3.2 ppb 10 min after smoking a cigarette.
Buda et al. (115) reported FENO to be 18,29,and 16% higher than
baseline 30, 45, and 60 min after smoking a cigarette, respectively.
The findings of Vardavas et al. (100) concerning FENO levels after
acute vaping are in direct opposition to what has been observed
immediately after smoking a cigarette (114, 115). These results
clearly demonstrate that acute vaping and acute smoking affect
pulmonary nitric oxide metabolism, and the associated airway
inflammatory responses, differently. From the available literature
it is not clear how vaping might affect pulmonary inflammatory
processes, but, as previously indicated, glycerin has been linked
to lipoid pneumonia (99), and nicotine is known to generate
endothelial dysfunction and systemic inflammation (16). Propy-
lene glycol mist has been shown to produce ocular and respiratory
irritation (116), and increase the risk of acquiring asthma (117),
although Robertson et al. (118) reported that long-term inhala-
tion of propylene glycol vapor by both monkeys and rats produced
no deleterious pulmonary effects and Laugesen et al. (9) found no
ill effects in humans. Bahl et al. (119) investigated the effects of a
number of e-cigarette refill fluids on cultured human embryonic
stem cells (hESCs), and human pulmonary fibroblasts (hPFs) and
found that nicotine in e-cigarette refill fluids had no effect on
hESC or hPF cytotoxicity at any concentration. However, they did
report a positive correlation between hESC cytotoxicity, and the
number and concentration of other chemicals used to flavor e-
cigarette refill fluids. Similar results were published by Romagna
et al. (120) who demonstrated that an extract of e-cigarette mist
was less cytotoxic to cultured murine fibroblasts than an extract of

Table 4 | Studies involving clinical and physiological effects of acute vaping.
Authors (Reference) Study design Subjects Study location Key finding
STUDIES REPORTING POSITIVE OR NEUTRAL IMPACT OF E-CIGARETTES AND VAPING ON HEALTH
Caponnetto et al.
(113)
Three case
reports
A 47-year old male
A 38-year old female
A 65-year old male
University of Catania, Catania, Italy Participants successfully switched
from conventional cigarettes to
e-cigarettes and then quit e-cigarettes.
Smoking cessation confirmed by
Bahl et al. (119) In vitro
cultures
Human embryonic stem cells,
and pulmonary fibroblasts
University of California, Riverside,
California
Nicotine in e-cigarette refill fluids had
no effect on the cytotoxicity of human
embryonic stem cells
Flouris et al. (121) Repeated-
measures
controlled
study
Thirty human smokers
(8 male) cycled through a
control session, active
smoking session, and active
vaping session
Fifteen never smokers
(8 male) cycled through a
control session, passive
smoking session and passive
vaping session
FAME Laboratory, Institute of
Human Performance and
Rehabilitation, Center for Research
and Technology, Trikala, Greece
Acute smoking, but not acute vaping,
induced increases in white blood cell
count, lymphocyte count and
granulocyte count
University of Thessaly, Trikala, and
Larissa, Greece
Palamas Health Center, Kardista,
Greece
University of Botswana, Botswana
University of Crete, Crete, Greece
University of Wolverhampton,
United Kingdom
Farsalinos and
Romagna (123)
Case report A 28-year old male with
chronic iodiopathic
neutrophilia
Onasis Cardiac Surgery Center,
Kallithea, Greece and Abich ABICH
S.r.l. Toxicological Laboratory,
Verbania, Italy
Smoking cessation and e-cigarette use
reversed symptoms of chronic
iodiopathic neutrophilia. Smoking
cessation was confirmed by exhaled
carbon monoxide
Flouris et al. (79) Repeated-
measures
controlled
study
Thirty human smokers (8
male) cycled through a control
session, active smoking
session and active vaping
session. Fifteen never
smokers (8 male) cycled
through a control session,
passive smoking session, and
passive vaping session
FAME Laboratory, Institute of
Human Performance and
Rehabilitation, Center for Research
and Technology, Trikala, Greece
Vaping produced smaller changes in
pulmonary function but similar
nicotinergic impact compared to
smoking
Romagna et al. (120) In vitro
cultures
Murine Fibroblasts ABICH S.R.L. Toxicological
Laboratory, Verbania, Italy
Extract of e-cigarette mist is less
cytotoxic than extract of cigarette
smoke to murine fibroblasts
STUDIES REPORTING NEGATIVE IMPACT OF E-CIGARETTES AND VAPING ON HEALTH
Bahl et al. (119) In vitro
cultures
Human embryonic stem cells,
and pulmonary fibroblasts
University of California, Riverside,
California
The number and concentration of
chemicals (other than nicotine) used to
flavor e-cigarette refill fluids increased
cytotoxicity
McCauly et al. (99) Case report A 42-year woman with
exogenous lipoid pneumonia
Legacy Good Samaritan Medical
Center, Portland, Oregon
Termination of e-cigarette use cleared
the exogenous lipoid pneumonia
Vardavas et al. (100) Laboratory-
based
intervention
study
Active vaping (experimental)
for 5 min in smokers (14 men)
versus passive vaping
(control) for 5 min in 10
smokers randomly selected
from the experimental group
Participants from a community in
Athens, Greece
Five minutes acute vaping-induced a
decrease in exhaled nitric oxide, and an
increase in airway resistance and
impedance in experienced smokers

tobacco cigarette smoke. A further indication that there are differ-
ences in the inflammatory responses between vapers and smokers
is illustrated in a study reporting an absence of increased inflam-
matory indices in smokers asked to vape for 30 min compared to
smokers who were asked to smoke for 30 min (121). Acute smok-
ing has long been known to increase white blood cell count, which
is a sign of acute inflammatory load (122). Flouris et al. (121)
were able to confirm elevations of white blood cell count, lym-
phocyte count, and granulocyte count in active smokers but not
in active vapers. Support for this is seen in a recently published
case report (123) where a 36-year-old male with a nine pack-
year history of smoking exhibited reversal of chronic idiopathic
neutrophilia symptoms after he quit smoking and started vaping.
Table4 summarizesthe studiesinvolving clinicaland physiological
effects of acute vaping.
CONCLUSION
Despite the popularity e-cigarettes have gained worldwide, very
little rigorous research has been done regarding the effects these
devices have on human health. This article reviews the existing
evidence-based literature, dealing with surveys soliciting personal
views on vaping; studies analyzing potential toxins and cont-
aminants in e-cigarette cartridges, solutions, and mist; reports
profiling nicotine content, delivery, and pharmacokinetics; and
clinical and physiological studies investigating the effects of acute
vaping. When compared to the harmful effects of smoking, these
studies suggest that vaping could be used as a possible “harm
reduction” tool. There is evidence supporting e-cigarettes as an
aide for smoking cessation, at least as successful as currently avail-
able FDA-approved NRTs. Less evidence exists to suggest that
e-cigarettes are effective in recovery from nicotine dependence.
More rigorous research is essential before any solid conclusions
can be drawn about the dangers, or usefulness of e-cigarettes. In
particular, more rigorous research is required delving into both
acute and long-term cardiopulmonary effects of vaping, espe-
cially those experiments comparing the effects of vaping with
those of smoking. E-cigarettes are fast becoming a new “tobacco”
industry(124)thatcouldreducetheincidenceof traditionalsmok-
ing. It is also possible that e-cigarettes may either decrease or
increase the incidence of nicotine addiction. Given these uncer-
tainties, will the availability of e-cigarettes provide for healthier
U.S. and world populations, as harm reductionists hope, or will
other more dangerous ill effects ultimately emerge? Health care
professionals must remain current with the literature concern-
ing e-cigarettes and vaping. Only then can they make informed
decisions aimed at maximizing human safety and minimizing the
potential ill effects e-cigarettes may have on their patients and the
public. Only then can the new challenge regarding e-cigarettes
and vaping in clinical medicine and public health be adequately
addressed.
ACKNOWLEDGMENTS
The author would like to thank the faculty and staff of the DeBusk
College of Osteopathic Medicine, Lincoln Memorial University
for graciously providing constructive criticism, comments, and
editorial assistance in the preparation of this manuscript.
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